OBJECTIVES: To better define the mechanisms which control insulin, glucagon, and somatostatin release from the normal pancreatic islet and the abnormalities which exist in the genetically diabetic animal, and to investigate possible methods for improving islet function in the diabetic. MODEL: Several sublines of highly inbred, genetically diabetic Chinese hamsters are noted for diabetes mellitus of the non-obese, insulin-deficient type. Both overtly diabetic and PREdiabetic animals in which the disease has not yet manifested itself will be studied. Normal, non-diabetic Chinese hamsters serve as controls. METHODS: The in vitro perfused pancreas preparation will be used to document the quantity and dynamic quality of insulin, glucagon, and somatostatin release. Collagenase-isolated islets will be used to study 45Ca efflux, 45Ca uptake, and simultaneous insulin release. Indirect parameters of pancreatic function (plasma and urine glucose, plasma hormone levels, insulin antibody titers, glucose and insulin tolerance, body weight, food consumption, and pancreatic hormone content) will be followed. The subcutaneously-implantable, drug-releasing minipump will be used for continuous infusion of insulin or other agents into diabetic animals for periods of 1-6 weeks. PROPOSED RESEARCH: To better define the site(s) of damage in the diabetic endocrine pancreas, hormone release and 45Ca handling will be studied in response to several different classes of agents (sugars, amino acids, cAMP-related agents, membrane depolarization, agents known to affect intracellular stores of calcium, calcium excess, etc.). Progressive changes in pancreatic function will be carefully followed in diabetic sublines starting at the earliest possible PREdiabetic stage and continuing on through overt diabetes. Effect of dietary changes and insulin therapy will be studied. Correlations among hormones released and metabolic state of the animal will be sought.